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The sponsor of a recent Phase II global study, conducted at more than 50 sites, invested in a centralized digital pathology core lab to ensure a homogenous and representative study population.
The sponsor of a recent Phase II global study, conducted at more than 50 sites, invested in a centralized digital pathology core lab to ensure a homogenous and representative study population. For this study, the lab, powered by Biomedical Systems, worked to confirm the pathological diagnoses of patients' disease states.
The investment proved advantageous, and the findings were startling: 30% of patients submitted for central review did not meet the inclusion criteria. Failure to properly classify its patient population can leave sponsors with a significantly underpowered study—rendering the drug manufacturer with inaccurate efficacy results, a failed study, and a heavy price tag.
To understand how the study sites, which relied on patient medical histories combined with site-prepared histology biopsy slides, approved patients who did not meet the inclusion criteria requires an understanding of the digital pathology evolution.
Before the advent of slide digitization, pathologists reviewed specimens on glass slides under microscopes. To secure multiple pathologists' interpretations, labs would prepare several sets of slides from the patient's tissue block—each slide containing a different level of tissue shipped to the reviewer. Variance in tissue levels triggered variability among inter-reader interpretations of the specimens. Subsequently, sponsors began leveraging digital pathology to provide reviewers with identical digital images of patients' tissues, effectively reducing variability.
In the referenced Phase II study, variability could explain the 30% discrepancy between internal site review and the central review process. With the study, pathology slides were reviewed at more than 50 sites; each of the sites employs its own pathologists. In addition, each site offers its own equipment and methods for slide collection and patient history documentation.
With centralized digital pathology, the study and its readers must follow rigorous, standardized processes focused solely on inclusion criteria. Pathologists may only assess the morphology depicted in the digital slide image sets, which reduce variability and bias.
For the Phase II global study, readers were trained on standardized equipment, scoring methodology, and the electronic case report form application. Each reader in the study viewed the exact same digital slide image sets. Readers followed proven project management practices and systems to ensure their assessment results were directly linked to the evaluation. The electronic case report form guided each of the readers through the same protocol-specific evaluation and grading scale.
After a reader completed each required field, he or she would enter a given password to apply a digital signature and date/time stamp to the completed record. The completed record was sequestered, preventing the reader from returning to the record or the digital slide image set. These processes effectively reduced variability, promoted homogenous analysis methodology across all readers, and ensured complete records were provided in a format conducive to statistical analysis.
Centralization and variability. By centralizing a study, sponsors and its study partners can typically decrease the number of pathologists needed to evaluate patients for inclusion. This reduction in pathologists lessens the variability associated with the inclusion assessments. In the study, the centralized lab effectively worked to significantly decrease the number of pathologists evaluating patients. Reviewer reduction was coupled with standardization—providing uniform training, equipment, and review processes to improve patient inclusion percentages and reduce variability.
Independent review and bias. In the study, the independent review, which is inherently part of the centralized review process, proved effective in ensuring only patients who met the protocol inclusion criteria were enrolled in the study.
In cases of site-selected inclusion, site pathologists review patients' history, test results, and histology primarily for patient care. Study inclusion criteria often serve as the site's secondary goal. The pathologists' expanded patient knowledge, which is important for patient care, can potentially hinder the clinical trial process by injecting unintended bias into the patient inclusion evaluation.
The readers were required to follow a centralized digital pathology process, and only focused on the morphology represented within the digital slide images. For the study, readers were blind to all extraneous patient information.
The impact of an underpowered study can cost drug manufacturers millions of dollars and their reputations. Centralized digital pathology, in this example, reduced bias and variability while increasing the probability of accurately assessing efficacy and statistically relevant data.
—Tim Callahan, PhD, Chief Scientific Officer, Biomedical Systems. Member of Applied Clinical Trials' Editorial Review Board.